Glymphatic system
Clearance of soluble proteins, metabolites and excess extracellular fluid is accomplished through convective bulk flow of ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.
[4] In a study published in 2012,[5] a group of researchers from the University of Rochester, headed by Maiken Nedergaard, used in-vivo two-photon imaging of small fluorescent tracers to monitor the flow of subarachnoid CSF into and through the brain parenchyma.
[citation needed] Astrocytes extend long processes that interface with neuronal synapses, as well as projections referred to as 'end-feet' that completely ensheathe the brain's entire vasculature.
Analysis of genetically modified mice that lacked the AQP4 gene revealed that the bulk flow-dependent clearance of interstitial solutes decreases by 70% in the absence of AQP4.
Based upon this role of AQP4-dependent glial water transport in the process of paravascular interstitial solute clearance, Iliff and Nedergaard termed this brain-wide glio-vascular pathway the "glymphatic system".
A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state.
On the basis of these findings, they hypothesized that the restorative properties of sleep may be linked to increased glymphatic clearance of metabolic waste products produced by neural activity in the awake brain.
[16][17] Collectively these diseases fall within a broad category referred to as proteinopathies due to the common assemblage of misfolded or aggregated intracellular or extracellular proteins.
[20] The 16 centuries of anatomists who came after Hippocrates and Galen may have missed identifying the CSF due to the prevailing autopsy technique of the time, which included severing the head and draining the blood before dissecting the brain.
[citation needed] For more than a century the prevailing hypothesis was that the flow of cerebrospinal fluid (CSF), which surrounds, but does not come in direct contact with the parenchyma of the CNS, could replace peripheral lymphatic functions and play an important role in the clearance of extracellular solutes.
[citation needed] As an alternative explanation to diffusion, Cserr and colleagues proposed that convective bulk flow of interstitial fluid from the brain parenchyma to the CSF was responsible for efficient waste clearance.
In a series of elegantly designed experiments in the 1980s and 1990s, researchers from New York University explored the microenvironment of the extracellular space using ion-selective micropipettes and ionophoretic point sources.
[30][28] Glymphatic flow was initially believed to be the complete answer to the long-standing question of how the sensitive neural tissue of the CNS functions in the perceived absence of a lymphatic drainage pathway for extracellular proteins, excess fluid, and metabolic waste products.
